This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (xe2x88x921 and xe2x88x922) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Bxe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Bxe2x80x9d) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [TARC, MIP-1xcex1, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d OR xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or xe2x80x9cCKR-6xe2x80x9d or xe2x80x9cCC-CKR-6xe2x80x9d) [LARC] (Baba et al., J. Biol. Chem.xe2x80x9d, 272, 14893-14898 (1997)); CCR-7 (or xe2x80x9cCKR-7xe2x80x9d or xe2x80x9cCC-CKR-7xe2x80x9d) [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or xe2x80x9cCKR-8xe2x80x9d or xe2x80x9cCC-CKR-8xe2x80x9d) [I-309, TARC, MIP-1xcex2] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or xe2x80x9cCKR-10xe2x80x9d or xe2x80x9cCC-CKR-10xe2x80x9d) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the past several decades with respect to substituted piperidines and pyrrolidines. These compounds have implicated in the treatment of a variety of disorders.
WO 98/25604 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors: 
wherein R1 is C1-6 alkyl, optionally substituted with functional groups such as xe2x80x94NR6CONHR7, wherein R6 and R7 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds are not considered part of the present invention.
WO 98/31364 describes disubstituted piperidines which are useful as modulators of chemokine receptors: 
wherein R1 is benzylpiperidine or benzylpyrrolidine. Such disubstituted piperidines ar not considered part of the present invention.
WO 96/26196 is directed to certain benzylpiperidines and piperazines as muscarinic antagonists: 
In these compounds as well as other muscarinic antagonists, the ring of R2 is linked directly to the piperidine containing Y and Z. The compounds of the present invention do not include compounds of this type.
WO 95/19344 discloses tachykinin antagonists of formula: 
wherein X is O or NR19, R1 and R2 are substituted phenyl, and R3 may be COR9, CONR10R11 and the like. Such compounds require this substitution at R1, R2, and X while R3 groups do not represent those of the present invention.
Other tachykinin antagonists include those of WO 97/22597, in which the two piperidine or pyrroline rings must be linked directly through a bond: 
U.S. Pat. No. 5,576,319 discloses a method of treatment for schizophrenia comprising administering a compound of formula: 
to a patient in need thereof. These compounds are not indicated as modulators of CCR3, and do not contain the necessary features of the present invention.
WO 97/06802 concerns oxido-squalene cyclase inhibitors of formula: 
and WO 98/35959 concerns similar heterocyclic derivatives of formula: 
wherein T1, T2, and T3 may be carbon or nitrogen, X may be methylene, Q is a carbocyclic ring, A may be absent and G is N or CH. Such compounds contain pyridine or pyridine derivatives directly off the piperidine rings. Further, the compounds of these references which bridge the pyridine analogously to the present invention require a carbonyl functionality in the linker.
Sulphonamide derivatives are implicated in WO 97/48681 as useful in the treatment of CNS disorders. The nitrogen bearing R1 and R2 of compounds of formula: 
may be taken together to form a piperidine ring, however, such rings may only be substituted when an additional nitrogen is contained in the ring formed by R1 and R2.
The foregoing reference compounds are readily distinguished structurally by either the nature of the terminal functionality, attachment chain, or possible substitution of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel piperidines and pyrrolidines as having activity toward the chemokine receptors.
Accordingly, one object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating allergic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula I: 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein M, J, K, L, Q, E, Y, and R4 are defined below are effective modulators of chemokine activity.
Thus, in a first embodiment, the present invention provides novel compounds of formula I: 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
J, K, and L are independently selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5; and
2) when M is absent, J is selected from CH2, CHR5, CHR13, and CR5R13;
E is xe2x80x94(CR7R8)xe2x80x94(CR9R10)vxe2x80x94;
Y is selected from: 
X is selected from NR14, O, and S;
Z is selected from C(O)R3, S(O)2R3, C(O)OR3, C(O)NR2R3, C(xe2x95x90NR1)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, C(xe2x95x90C(CN)2)NR2R3, and (CRxe2x80x2Rxe2x80x2)t-phenyl substituted with 0-5 R15;
Rxe2x80x2, at each occurrence, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R15e;
R1 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2)wphenyl;
R2 is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R2a;
R2a, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR2bR2b, (CH2)rOH, (CH2)rOR2c, (CH2)rSH, (CH2)rSR2c, (CH2)rC(O)R2b, (CH2)rC(O)NR2bR2b, (CH2)rNR2bC(O)R2b, (CH2)rC(O)OR2b, (CH2)rOC(O)R2c, (CH2)rCH(xe2x95x90NR2b)NR2bR2b, (CH2)rNHC(xe2x95x90NR2b)NR2bR2b, (CH2)rS(O)pR2c, (CH2)rS(O)2NR2bR2b, (CH2)rNR2bS(O)2R2c, and (CH2)rphenyl;
R2b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R2c, at each occurrence, is selected from C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
R3 is selected from a CR3xe2x80x2R3xe2x80x3R3xe2x80x3, (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R15 and a (CR3xe2x80x2R3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R3xe2x80x2 and R3xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4axe2x80x2, (CH2)qC(O)OR4b, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R4c;
R4a and R4axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, (CH2)rC3-6 cycloalkyl, C2-8 alkynyl, and phenyl;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4axe2x80x2, and (CH2)rphenyl;
R5 is selected from a (CR5xe2x80x2R5xe2x80x3)txe2x80x94C3-10 carbocyclic residue substituted with 0-5 R16 and a (CR5xe2x80x2R5xe2x80x3)t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
R5xe2x80x2 and R5xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rNR6aR6a, (CH2)rOH, (CH2)rOR6b, (CH2)rSH, (CH2)rSR6b, (CH2)rC(O)OH, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6axe2x80x2, (CH2)rNR6dC(O)R6a, (CH2)rC(O)OR6b, (CH2)rOC(O)R6b, (CH2)rS(O)pR6b, (CH2)rS(O)2NR6aR6axe2x80x2, (CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R7 is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR7d, (CH2)qSR7d, (CH2)qNR7aR7axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R7b, (CH2)rC(O)NR7aR7axe2x80x2, (CH2)qNR7aC(O)R7a, (CH2)rC(O)OR7b, (CH2)qOC(O)R7b, (CH2)qS(O)pR7b, (CH2)qS(O)2NR7aR7axe2x80x2, (CH2)qNR7aS(O)2R7b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R7c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7c;
R7a and R7axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR7fR7f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R7b, (CH2)rC(O)NR7fR7f, (CH2)rNR7fC(O)R7a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R7b, (CH2)rC(xe2x95x90NR7f)NR7fR7f, (CH2)rS(O)pR7b, (CH2)rNHC(xe2x95x90NR7f)NR7fR7f, (CH2)rS(O)2NR7fR7f, (CH2)rNR7fS(O)2R7b, and (CH2)rphenyl substituted with 0-3 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 R7e, alkenyl, alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R7c;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl , F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
R8 is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)tphenyl substituted with 0-3 R8a;
R8a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
alternatively, R7 and R8 join to form C3-7 cycloalkyl, or xe2x95x90NR8b;
R8b is selected from H, C1-6 alkyl, C3-6 cycloalkyl, OH, CN, and (CH2)r-phenyl;
R9 is independently selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CH2)rOH, (CH2)rSH, (CH2)rOR9d, (CH2)rSR9d, (CH2)rNR9aR9axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9aC(O)R9a, (CH2)rNR9aC(O)H, (CH2)rC(O)OR9b, (CH2)rOC(O)R9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9axe2x80x2, (CH2)rNR9aS(O)2R9b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R9c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c;
R9xe2x80x2 is independently selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CH2)rOH, (CH2)rSH, (CH2)rOR9d, (CH2)rSR9d, (CH2)rNR9aR9axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9aC(O)R9a, (CH2)rNR9aC(O)H, (CH2)rC(O)OR9b, (CH2)rOC(O)R9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9axe2x80x2, (CH2)rNR9aS(O)2R9b, C1-6 haloalkyl, (CH2)rxe2x80x94C3-6 cycloalkyl, (CH2)q-phenyl substituted with 0-5 R9c, and a (CH2)q-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR9fR9f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R9b, (CH2)rC(xe2x95x90NR9f)NR9fR9f, (CH2)rS(O)pR9b, (CH2)rNHC(xe2x95x90NR9f)NR9fR9f, (CH2)rS(O)2NR9fR9f, (CH2)rNR9fS(O)2R9b, and (CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R9c;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
R10 is independently selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CH2)rOH, (CH2)rOR10d, (CH2)rSR10d, (CH2)rNR10aR10axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R10b, (CH2)rC(O)NR10aR10axe2x80x2, (CH2)rNR10aC(O)R10a, (CH2)rNR10aC(O)H, (CH2)rC(O)OR10b, (CH2)rOC(O)R10b, (CH2)rS(O)pR10b, (CH2)rS(O)2NR10aR10axe2x80x2, (CH2)rNR10aS(O)2R10b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R10c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10c;
R10a and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R10e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR10fR10f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R10b, (CH2)rC(O)NR10fR10f, (CH2)rNR10fC(O)R10a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R10b, (CH2)rC(xe2x95x90NR10f)NR10fR10f, (CH2)rS(O)pR10b, (CH2)rNHC(xe2x95x90NR10f)NR10fR10f, (CH2)rS(O)2NR10fR10f, (CH2)rNR10fS(O)2R10b, and (CH2)rphenyl substituted with 0-3 R10e;
R10d, at each occurrence, is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R10c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R10c;
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR10fR10f, and (CH2)rphenyl;
R10f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
with the proviso that when R10 is xe2x80x94OH, R9 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
alternatively, R9 and R10 join to form C3-7 cycloalkyl;
R11 is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR11d, (CH2)qSR11d, (CH2)qNR11aR11axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)R11a, (CH2)rC(O)OR11b, (CH2)qOC(O)R11b, (CH2)qS(O)pR11b, (CH2)qS(O)2NR11aR11axe2x80x2, (CH2)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11xe2x80x2 is selected from H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)qOH, (CH2)qSH, (CH2)qOR11d, (CH2)qSR11d, (CH2)qNR11aR11axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)R11a, (CH2)rC(O)OR11b, (CH2)qOC(O)R11b, (CH2)qS(O)pR11b, (CH2)qS(O)2NR11aR11axe2x80x2, (CH2)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-6 cycloalkyl, (CH2)q-phenyl substituted with 0-5 R11c, and a (CH2)q-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11a and R11axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11fR11f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11fR11f, (CH2)rNR11fC(O)R11a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R11b, (CH2)rC(xe2x95x90NR11f)NR11fR11f, (CH2)rNHC(xe2x95x90NR11f)NR11fR11f, (CH2)rS(O)pR11b, (CH2)rS(O)2NR11fR11f, (CH2)rNR11fS(O)2R11b, and (CH2)rphenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 R11e, C2-6 alkenyl, C1-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl;
R11f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
R12 is selected from H, C1-6 alkyl, (CH2)qOH, (CH2)rC3-6 cycloalkyl, and (CH2)tphenyl substituted with 0-3 R12a;
R12a, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R13, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)wCF3, CH2NR13aR13axe2x80x2, (CH2)rOH, (CH2)rOR13b, (CH2)rSH, (CH2)rSR13b, (CH2)wC(O)OH, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13axe2x80x2, (CH2)rNR13dC(O)R13a, (CH2)wC(O)OR13b, (CH2)rOC(O)R13b, (CH2)wS(O)pR13b, (CH2)wS(O)2NR13aR13axe2x80x2, (CH2)rNR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
R13a and R13axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR13dR13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R14 is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C(O)NR14aR14axe2x80x2, C(O)R14b, C(O)OC1-4 alkyl, (CH2)rS(O)pR14b, (CH2)rphenyl substituted with 0-3 R14c;
R14a and R14axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R14c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14c;
R14b, at each occurrence, is selected from C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R14c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14c; and
R14c, at each occurrence, is selected from C1-6 alkyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, (CH2)wphenyl;
R15, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(xe2x95x90NR15f)NR15aR15axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR15f)NR15fR15f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R15e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R15e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR15fR15f, and (CH2)rphenyl;
R15f, at each occurrence, is selected from H, C1-5 alkyl, C3-6 cycloalkyl, and phenyl;
R16, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(xe2x95x90NR16f)NR16aR16axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR16f)NR16fR16f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16a and R16a, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R16e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16d, at each occurrence, is selected from C2-8 alkenyl, C2-8 alkynyl, C1-6 alkyl substituted with 0-3 R16e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16e;
R16e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR16fR16f, and (CH2)rphenyl;
R16f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
v is selected from 0, 1, and 2;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and
p is selected from 1, 2, and 3.
In a preferred embodiment, the present invention provides novel compounds of formula I, wherein:
Z is selected from C(O)R3, S(O)2R3, C(O)OR3, C(O)NR2R3, C(xe2x95x90NR1)NR2R3, and (CRxe2x80x2Rxe2x80x2)t-phenyl substituted with 0-5 R15;
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4axe2x80x2, and (CH2)rphenyl;
alternatively, R4 joins with R7, R9, or R11 to form a 5, 6 or 7 membered piperidinium spirocycle substituted with 0-3 Ra;
R2 is independently selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rOH, (CH2)rOR6b, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6axe2x80x2, (CH2)rNR6dC(O)R6a, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c,
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R7, is selected from H, C1-3 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)qOH, (CH2)qOR7d, (CH2)qNR7aR7axe2x80x2, (CH2)rC(O)R7b, (CH2)rC(O)NR7aR7a, (CH2)qNR7aC(O)R7a, C1-6 haloalkyl, (CH2)rphenyl with 0-2 R7c;
R7a and R7axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, a (CH2)rphenyl substituted with 0-3 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)rphenyl substituted with 0-3 R7e;
R7c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR7fR7f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rC(O)R7b, (CH2)rC(O)NR7fR7f, (CH2)rNR7fC(O)R7a, (CH2)rS(O)pR7b, (CH2)rS(O)2NR7fR7f, (CH2)rNR7fS(O)2R7b, and (CH2)rphenyl substituted with 0-2 R7e;
R7d, at each occurrence, is selected from C1-6 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)rphenyl substituted with 0-3 R7e;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl;
R8 is H or joins with R7 to form C3-7 cycloalkyl or xe2x95x90NR8b;
R9, is selected from H, C1-3 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)rOH, (CH2)rOR9d, (CH2)rNR9aR9axe2x80x2, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9aC(O)R9a, C1-6 haloalkyl, (CH2)rphenyl with 0-2 R9c, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R9xe2x80x2, is selected from H, C1-3 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)rOH, (CH2)rOR9d, (CH2)rNR9aR9axe2x80x2, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9aC(O)R9a, C1-6 haloalkyl, (CH2)rphenyl with 0-2 R9c, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, a (CH2)rphenyl substituted with 0-3 R9e;
R9b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)rphenyl substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR9fR9f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9a, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9fR9f, (CH2)rNR9fS(O)2R9b, and (CH2)rphenyl substituted with 0-2 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)rphenyl substituted with 0-3 R9e;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl;
R9f, at each occurrence, is selected from H, C1-5 alkyl and C3-6 cycloalkyl;
R10 is H or joins with R9 to form C3-7 cycloalkyl;
R11, is selected from H, C1-3 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)qOH, (CH2)qOR11d, (CH2)qNR11aR11axe2x80x2, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)R11a, C1-6 haloalkyl, (CH2)rphenyl with 0-2 R11c, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R11xe2x80x2, is selected from H, C1-3 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)qOH, (CH2)qOR11d, (CH2)qNR11aR11axe2x80x2, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)R11a, C1-6 haloalkyl, (CH2)rphenyl with 0-2 R11c, (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R11a and R11axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, a (CH2)rphenyl substituted with 0-3 R11e;
R11b, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)rphenyl substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11fR11f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rC(O)R11b, (CH2)rC(O)NR11fR11f, (CH2)rNR11fC(O)R11a, (CH2)rS(O)pR11b, (CH2)rS(O)2NR11fR11f, (CH2)rNR11fS(O)2R11b, and (CH2)rphenyl substituted with 0-2 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl, (CH2)rC3-6 cycloalkyl, (CH2)rphenyl substituted with 0-3 R11e;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl;
R11f, at each occurrence, is selected from H, C1-5 alkyl and C3-6 cycloalkyl;
R12 is H or joins with R11 to form C3-7 cycloalkyl;
R13, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, (CH2)qNR13aR13axe2x80x2, (CH2)qOH, (CH2)qOR13b, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13axe2x80x2, (CH2)qNR13dC(O)R13a, (CH2)wS(O)2NR13aR13axe2x80x2, (CH2)qNR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
R13a and R13axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, and (CH2)rNR13dR13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
v is selected from 1 and 2;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
In a more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
R3 is selected from a (CR3xe2x80x2H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and
R5 is selected from (CR5xe2x80x2H)t-phenyl substituted with 0-5 R16; and a (CR5xe2x80x2H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In a further more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
Y is selected from: 
In an even further more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
R9 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R10 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R11 is selected from H, C1-4 alkyl, and (CH2)rphenyl; and
R12 is selected from H, C1-4 alkyl, and (CH2)rphenyl.
In an even further more preferred embodiment, the present invention provides novel compounds of formula I-i: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl , Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-i, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15a, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula I-i, the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In another even more preferred embodiment, the present invention provides novel compounds of formula I-ii: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In another further more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
Y is selected from: 
In an even more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
R9 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R10 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R11 is selected from H, C1-4 alkyl, and (CH2)rphenyl; and
R12 is selected from H, C1-4 alkyl, and (CH2)rphenyl.
In an even more preferred embodiment, the present invention provides novel compounds of formula I-i: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16a, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-i, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fCO(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e.
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula (I-i), the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In an even more preferred embodiment, the present invention provides novel compounds of formula I-ii: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)pR16b, (CH2)rS(O)R16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C16 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In another further more preferred embodiment, the present invention provides novel compounds of formula I, wherein: 
Y is selected from
In an even further more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
R9 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R10 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R11 is selected from H, C1-4 alkyl, and (CH2)rphenyl; and
R12 is selected from H, C1-4 alkyl, and (CH2)rphenyl.
In an even further more preferred embodiment, the present invention provides novel compounds of formula I-i: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-i, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)C(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, and (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula I-i, the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In another even further more preferred embodiment, the present invention provides novel compounds of formula I-ii: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl , F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, and (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In another further more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
Y is selected from: 
In an even further more preferred embodiment, the present invention provides novel compounds of formula I, wherein:
R9 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R10 is selected from H, C1-4 alkyl, and (CH2)rphenyl;
R11 is selected from H, C1-4 alkyl, and (CH2)rphenyl; and
R12 is selected from H, C1-4 alkyl, and (CH2)rphenyl.
In an even further more preferred embodiment, the present invention provides novel compounds of formula I-i: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-i, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula I-i, the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In another even further more preferred embodiment, the present invention provides novel compounds of formula I-ii: 
wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, (CH2)rphenyl substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In a preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
R3 is a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, and adamantyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl;
R5 is CH2-phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
In a more preferred embodiment of formula I-ii, the present invention provides novel compounds, wherein:
E is xe2x80x94CH2xe2x80x94; and 
Y is
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein:
R4 is absent; and
R9, R9xe2x80x2, R10, R11, R11xe2x80x2, R12 and R13 are H.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein: R5 is CH2-phenyl substituted with 0-3R16.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein R3 is selected from a carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from phenyl and C3-6 cycloalkyl; and a heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein:
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein E is xe2x80x94CR7R8xe2x80x94. In other preferred embodiments, E is xe2x80x94CH2xe2x80x94.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein Z is selected from C(O)NR2R3, C(xe2x95x90NR1)NR2R3, C(xe2x95x90CHCN)NR2R3, C(xe2x95x90CHNO2)NR2R3, and C(xe2x95x90C(CN)2)NR2R3.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein:
R6 is H; and
when K is CHR5, either:
1) M is absent, or
2) Z is other than C(O)NR2R3.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein Y is selected from: 
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein Y is selected from: 
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein:
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, CN, OH, OCF3, (CH2)rOR16d, (CH2)rC(O)R16b;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein R16 is selected from F, Cl, Br, OCF3, and CF3.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein:
R15, at each occurrence, is selected from CN,C(O)R15b, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e; and
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein:
J and Q are CH2; and
M is absent or CH2.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein K is CH2.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein Z is selected from C(xe2x95x90NR1)NR2R3.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein Z is selected from C(xe2x95x90C(CN)2)NR2R3.
In certain more preferred embodiments of formula I, the present invention provides novel compounds, wherein Z is selected from C(xe2x95x90NCN)NHR3.
In certain preferred embodiments of formula I, the present invention provides novel compounds, wherein R3 is phenyl substituted with 0-3 R15.
In certain even more preferred embodiments, the present invention provides novel compounds of formula I selected from:
(+/xe2x88x92)-N-phenyl-3-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-3-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(1-adamantyl)-3-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
N-phenyl-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
N-(3-cyanophenyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
N-(1-adamantyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
N-(3-methoxyphenyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
N-(3-carboethoxyphenyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]-1-piperidinecarboxamide,
1-benzoyl-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-phenylacetyl-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-(3,4-dimethoxybenzoyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-(3,5-dichlorobenzoyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-(3,5-difluorobenzoyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-(3,5-dimethoxybenzoyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-(3,4-methylenedioxybenzoyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-(2-thiophenesulfonyl)-4-[[(4-(phenylmethyl)-1-piperidinyl]methyl]-piperidinecarboxamide,
1-(3-methoxyphenylacetyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
1-(4-methoxyphenylacetyl)-4-[[4-(phenylmethyl)-1-piperidinyl]methyl]piperidine,
(+/xe2x88x92)-N-phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(1-adamantylphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(1-adamantylphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-1-phenylsulfonyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-piperidinecarboxamide,
(+/xe2x88x92)-1-benzoyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-1-benzyloxycarbonyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-pyrrolidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-pyrrolidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-pyrrolidinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-pyrrolidinecarboxamide,
(+/xe2x88x92)-N-(4-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-pyrrolidinecarboxamide,
(+/xe2x88x92)-N-(1-adamantylphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-pyrrolidinecarboxamide,
(+/xe2x88x92)-N-phenyl-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-carboethoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(1-adamantylphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-phenyl-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-carboethoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(1-adamantylphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyano phenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-4-morpholinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-4-morpholinecarboxamide,
(+/xe2x88x92)-N-(4-carboethoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-4-morpholinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-4-morpholinecarboxamide,
(+/xe2x88x92)-N-(1-adamantylphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-4-morpholinecarboxamide,
(+/xe2x88x92)-N-phenyl-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-4-morpholinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-4-morpholinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-hydroxy-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-hydroxy-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-hydroxy-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-hydroxy-1-piperidinecarboxamide,
(+/xe2x88x92)-N-phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-hydroxy-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-hydroxy-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-phenylmethyl-1-piperidine-carboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-N-phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(cis)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(cis)-N-(3-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(cis)-N-(4-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(cis)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(cis)-N-phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(cis)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(trans)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(trans)-N-(3-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(trans)-N-(4-carboethoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(trans)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(trans)-N-phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(trans)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-(trans)-N-(3-acetylphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-2-phenylmethyl-1-piperidinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3,4-dihydro-2(1H)isoquinolinecarboxamide,
(+/xe2x88x92)-N-(phenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3,4-dihydro-2(1H)isoquinolinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3,4-dihydro-2(1H)isoquinolinecarboxamide,
(+/xe2x88x92)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1,2,3,4-tetrahydro-2-(phenylacetyl)isoquinoline,
(+/xe2x88x92)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-1,2,3,4-tetrahydro-2-(phenylmethylsulfonyl)isoquinoline,
(+/xe2x88x92)-Phenyl-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3,4-dihydro-2(1H)isoquinolinecarboxylate,
(+/xe2x88x92)-N-(4-cyanophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3,4-dihydro-2(1H)isoquinolinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-3,4-dihydro-2(1H)isoquinolinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[2-[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-3-[[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-1,2,3,4-tetrahydro-2-(phenylsulfonyl)isoquinoline,
(+/xe2x88x92)-N-(4-fluorophenyl)-3-[2-[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(phenyl)-3-[2-[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-3-[[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-1,2,3,4-tetrahydro-2-(2-thiophenesulfonyl)isoquinoline,
(+/xe2x88x92)-3-[[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-1,2,3,4-tetrahydro-2-(phenacetyl)isoquinoline,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[2-[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(phenyl)-3-[2-[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-3-[2-[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-3-[2-[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-3-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-1,2,3,4-tetrahydro-2-(phenylmethylsulfonyl)isoquinoline,
(+/xe2x88x92)-Phenyl-3-[2-[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-3-[2-[4-[(phenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(3-carboethoxyphenyl)-3-[2-[4-[(4-fluorophenyl)methyl]-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(3-cyanophenyl)-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)phenylsulfonyl isoquinoline,
(+/xe2x88x92)-N-(4-fluorophenyl)-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(phenyl)-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(3-methoxyphenyl)-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-Phenyl-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate,
(+/xe2x88x92)-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)phenacetyl isoquinoline,
(+/xe2x88x92)-N-(3-cyanophenyl)-4-[2-[4-(4-fluorophenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-4-[2-[4-(4-fluorophenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-[phenyl]sulfonyl isoquinoline,
(+/xe2x88x92)-4-[2-[4-(4-fluorophenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)[phenacetyl]isoquinoline,
(+/xe2x88x92)-4-[2-[4-(4-fluorophenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-[phenylmethyl]sulfonylisoquinoline,
(+/xe2x88x92)-N-(4-carbethoxyphenyl)-4-[2-[4-(4-fluorophenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(+/xe2x88x92)-N-(4-fluorophenyl)-4-[2-[4-(phenylmethyl)-1-piperidinyl]ethyl]-3,4-dihydro-2(1H)-isoquinolinecarboxamide,
(2R)-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-4-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]morpholine,
(2R)-N-(3-acetylphenyl)-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-4-morpholinecarboxamide,
(2R)-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-N-(3-methoxyphenyl)-4-morpholinecarboxamide,
(2R)-N-(3-cyanophenyl)-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-4-morpholinecarboxamide,
(2R)-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-N-(4-fluorophenyl)-4-morpholinecarboxamide,
(2R)-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-N-phenyl-4-morpholinecarboxamide,
(2R)-N-(3-cyanophenyl)-2-{[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl}-4-morpholinecarboxamide,
(2R)-N-(3-acetylphenyl)-2-{[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl}-4-morpholinecarboxamide,
(2R)-N-(3-acetylphenyl)-2-{[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl}-N-phenyl-4-morpholinecarboxamide,
3-{[3-(4-fluorobenzyl)-1-pyrrolidinyl]methyl}-N-phenyl-1-piperidinecarboxamide,
N-(3-cyanophenyl)-3-{[3-(4-fluorobenzyl)-1-pyrrolidinyl]methyl}-1-piperidinecarboxamide,
N-(3-acetylphenyl)-3-{[3-(4-fluorobenzyl)-1-pyrrolidinyl]methyl}-1-piperidinecarboxamide,
3-{[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl}-N-phenyl-1-piperidinecarboxamide,
N-(3-cyanophenyl)-3-{[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl}-1-piperidinecarboxamide,
N-(3-acetylphenyl)-3-{[(3S)-3-(4-fluorobenzyl)piperidinyl]methyl}-1-piperidinecarboxamide,
tert-butyl 4-[(3-cyanoanilino)carbonyl]-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxylate,
N-(3-cyanophenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide dihydrochloride,
4-benzyl-N-(3-cyanophenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide,
4-acetyl-N-(3-acetylphenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide,
tert-butyl 4-[(anilino)carbonyl]-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxylate,
tert-butyl 4-[(3-methoxyanilino)carbonyl]-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxylate,
tert-butyl 4-[(3-acetylanilino)carbonyl]-2-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxylate,
3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-N-phenyl-1-piperazinecarboxamide dihydrochloride,
3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-N-(3-methoxyphenyl)-1-piperazinecarboxamide dihydrochloride
N-(3-acetylphenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide dihydrochloride; and
4-benzyl-N-(3-cyanophenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide.
In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for treating or preventing inflammatory disorders, such as, but not limited to, allergic disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin""s disease, and colonic carcinoma.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Ra) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ra, then said group may optionally be substituted with up to two Ra groups and Ra at each occurrence is selected independently from the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-8 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. xe2x80x9cC3-6 cycloalkylxe2x80x9d is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptl in the case of C7 cycloalkyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)).
The compounds of Formula I can also be quaternized by standard techniques such as alkylation of the piperidine or pyrrolidine with an alkyl halide to yield quaternary piperidinium salt products of Formula I. Such quaternary piperidinium salts would include a counterion. As used herein, xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, xcex2-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl; phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amine prodrugs the amine group is attached to a group selected from OH, C1-4 alkoxy, C6-10 aryloxy, C1-4 alkoxycarbonyl, C6-10 aryloxycarbonyl, C6-10 arylmethylcarbonyl, C1-4 alkylcarbonyloxy C1-4 alkoxycarbonyl, and C6-10 arylcarbonyloxy C1-4 alkoxycarbonyl. More preferred prodrugs are OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are incorporated in their entirety by reference.
The novel compounds of Formula I may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by-one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the edict molecule must be compatible with the reagents and reactions proposed. Not all compounds of Formula I falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must be used. 
Compounds of Formula I, wherein R4 is present as defined by the scope, may be prepared by procedures depicted in Scheme 1 from compounds of Formula I in which R4 is absent. The quaternary salts of Formula I can be synthesized by alkylation with an alkylhalide such as methyl iodide, benzyl bromide, bromoacetate, etc. in a suitable solvent such as THF, DMF, DMSO, etc. at room temperature to reflux temperature of the solvent. The N-oxides of Formula I can be made by the general protocols of Deady, Syn. Comm. 1977, 7, 509 and references therein, with minor modification depending on the substitution of Formula I which should be readily recognized by one skilled in the art. The N-oxides are created by oxidation with mCPBA in an inert solvent such as methlene chloride. 
Compounds of Formula I, wherein Z is CRxe2x80x2Rxe2x80x2R3, may be prepared by procedures depicted in Scheme 2. Reductive alkylation of Formula II, whose preparations are described later, with an aldehyde or ketone is carried out under conditions known in the art, for example, catalytic hydrogenation with hydrogen in the presence of palladium or platinum or with reducing agents such as sodium triacetoxy-borohydride. Alternatively, a similar transformation can be accomplished with an alkylating agent ZX where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. in the presence of a base such as triethylamine, pyridine, etc. in acetonitrile, DMF, DMSO, etc. at room temperature to reflux temperature of the solvent. 
Compounds of Formula I, wherein Z is either COR3, CO2R3, CONR2R3, or SO2R3, may be prepared as shown in Scheme 2. Compounds in which D is a bond, O or NR2 may be synthesized by reacting Formula II with Formula III, wherein B is a good leaving such as but not limited to Cl, Br, or imidazole, in the presence of a base such as, but not limited to, triethylamine or pyridine. Alternatively, Formula II may be reacted with an isocyante of Formula V to provide compounds of Formula I where Z is CONHR3. Alternatively, Formula II may be reacted Formula IV, wherein B is a good leaving such as but not limited to Cl, Br, or imidazole, in the presence of a base such as, but not limited to, triethylamine or pyridine to provide compounds of Formula I where Y is SO2R3. 
Preparation of intermediates of Formula II are depicted in Scheme 4. Reductive alkylation of the intermediates of Formula VI, whose preparations are described later if not commercially available, are reacted with compounds of Formula VII, whose preparations are described later if not commercially available, wherein amine on Y is protected with an amine protecting group (P) well familiar to those skilled in the art, and typical examples may be found in Greene, T and Wuts, P. G. M., Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991 and references therein, is carried out under conditions known in the art, for example catalytic hydrogenation with hydrogen in the presence of palladium or platinum or with reducing agents such as sodium triacetoxyborohydride. The protecting group P is removed using the appropriate reagents, well familiar to those skilled in the art, and typical examples may be found in Greene, T and Wuts, P. G. M., Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991, which provides the intermediates of Formula II. Alternatively, compounds of Formula II can be made by alkylating Formula VI with compounds of Formula VIII, as seen in Scheme 5, where the alcohol has been convert to a leaving group such as mesylate, tosylate, triflate, etc. by conditions well familiar to one skilled in the art.
The synthesis of the substituted and unsubstituted pyrrolidines, piperidines, piperazines, and morpholines of Formula VI and VII may be achieved by methods known in the art and are illustrated in the following schemes. 
The monosubstituted pyrrolidines and piperidines of Formula VII may be synthesized by procedures depicted in Scheme 5. It is understood that the chemistry is shown for only one position on the piperidine ring and that similar transformations may be preformed on other ring positions for both piperidine and pyrrolidine. The amino group of Formula VIII can be reacted with the appropriate reagents to protect the amine functionality, typical examples may be found in Greene, T and Wuts, P. G. M. The alcohol can be oxidized to either an aldehyde of Formula VII or an acid of Formula IX for further elaboration as shown in Scheme 5. Examples of oxidizing agents and conditions for aldehyde or acid formation are well familiar to those skilled in the art and typical examples may be found in Richard C. Larock, Comprehensive Organic Transformations, VCH Publishers, New York, 1989 and references therein. The acid of Formula IX can be converted to the methyl ester of Formula X with diazomethane in a inert solvent such as ether, THF, etc. at room temperature. The methyl ester can be treated with methyoxymethylamine precomplexed with trimethylaluminum to yield the Weinreb amide, as described in Taschner and Cyr, Tetrahedron Lett. 1990, 31, 5297 and references therein which than can be treated R7-M where M is a metal such as lithium, magnesium, etc. in an inert solvent such as THF, ether, etc. at xe2x88x9278xc2x0 C. to room temperature to yield compounds of Formula VII. Alternatively, when n=1 then the methyl ester can be treated with a base such as LDA, KHMDS, LHMDS, etc. in THF, ether, dioxane, etc., at xe2x88x9278xc2x0 C. to room temperature and an alkylating agent R9X where X is a halide, mesylate, triflate, etc. to yield compounds of Formula XI. This process can be repeated to incorporate R10 if necessary. Compounds of Formula XI can be convert to compounds of Formula VII as by methods described above. 
The monosubstituted pyrrolidines and piperidines of Formula VI may be synthesized by procedures depicted in Scheme 6. It is understood that the chemistry is shown for only one position on the piperidine ring and that similar transformations may be preformed on other ring positions for both piperidine and pyrrolidine. Formula XII can be treated under Wittig reaction conditions followed by reduction and deprotection under acidic conditions to yield compounds of Formula VI employing reactions well familiar to those skilled in the art. Alternatively, compounds of Formula VII can be used in place of Formula XII to create further embodiments of compounds of Formula VI. 
The gem-disubstituted pyrrolidines and piperidines of Formula VI and VIII may be synthesized by procedures depicted in Scheme 7. It is understood by one skilled in the art that some of the steps in this scheme can be rearranged. It is also understood that gem-disubstitution is only shown for only one position on the piperidine ring and that similar transformations may be performed on other carbon atoms as well, both for piperidine and pyrrolidine. Thus, BOC-3-carboethoxypiperidine may be alkylated employing a base such as LDA, KHMDS, LHDMS, etc., in THF, ether, dioxane, etc. at xe2x88x9278xc2x0 C. to room temperature and an alkylating agent R6X or R9X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to yield Formula XIII. Reduction using DIBAL, for example, leads to compounds of Formula VIII which can be further elaborated into compounds of Formula VII as described in Scheme 5. Alternatively, reduction using DIBAL, for example, followed by oxidation such as a Swern oxidation (S. L. Huang, K. Omura, D. Swern J. Org. Chem. 1976, 41, 3329-32) yields Formula XIV. Wittig olefination followed by acidic deprotection yields compounds of Formula VI. Alternatively, reduction of the Wittig adduct with H2 which may be deprotected under acidic conditions to yield compounds of Formula VI. Alternatively, reaction of Formula XIV with an alkyllithium or Grignard reagent yields Formula XV which may be reduced catalytically or with Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) if R5*(R5*=R5 or a precursor thereof) is aromatic to yield Formula XVI. If 5* is not aromatic, then the OH may be reduced by the method of Barton (Barton, D. H. R.; Jaszberenyi, J. C. Tet. Lett. 1989, 30, 2619 and other references therein). Once tosylated, the alcohol can also be displaced with dialkyllithium cuprates (not shown) (Hanessian, S.; Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831). Acidic deprotection yields compounds of Formula VI. 
The gem-disubstituted pyrrolidines and piperidines in which R9 is a hydroxy group may also be synthesized by procedures depicted in Scheme 8. It is understood that gem-disubstitution is only shown for only one position on the piperidine ring and that similar transformations may be performed on other carbon atoms as well, both for piperidine and pyrrolidine. CBZ-3-piperidone can be treated under Wittig reaction conditions well familiar to those skilled in the art to yield alkene compounds which then can be treated with mCPBA in an inert solvent such as methylene chloride to yield Formula VII. The epoxide can then be opened with compounds of Formula VI in solvents such as acetonitrile, DMF, DMSO, etc. at room temperature to reflux temperature of the solvent with pyrrolidine in toluene, THF, ether, dioxane, etc. at room temperature to the reflux temperature. The protecting group can be removed under conditions known in the art, for example catalytic hydrogenation with hydrogen in the presence of palladium or platinum to yield compounds of Formula II. 
The 2,3-disubstituted pyrrolidines and piperidines of Formula VII may be synthesized as shown in Scheme 9. This procedure essentially follows the general protocols of Brubaker and Colley, J. Med. Chem. 1986, 29, 1528 and references therein, with minor modification depending R11 which should be readily recognized by one skilled in the art. CBZ-3-piperidone can be treated with pyrrolidine in toluene, THF, ether, dioxane, etc. at room temperature to the reflux temperature of the solvent followed by an alkylating agent R11-X where X is a halide, mesylate, triflate, etc. in THF, acetonitrile, dioxane, etc. at room temperature to the reflux temperature of the solvent and then treated to acidic hydrolysis conditions to yield compounds of Formula XVII. Formula XVII can then be treated under Wittig reaction conditions well familiar to those skilled in the art followed by acid treatment to yield compounds of Formula VII. 
The 2,3-disubstituted pyrrolidines and piperidines of Formula VI and VIII may also be synthesized as shown in Scheme 10. This procedure essentially follows the general protocols of Micouin et. al., Tetrahedron Lett. 1996, 37, 849 and references therein, with minor modification depending on A and B which should be readily recognized by one skilled in the art. For compounds of the general Formula VI, Intermediate 1 can be treated with a base such as s-BuLi, etc. and an alkylating agent Axe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate R5, as defined in the scope. The compound can be treated with sodium hydride followed by B-metal which can a grinard reagent to incorporate the B group, R13 as defined in the scope. The synthesis is finished by the reduction of the lactam to the amine with a reagent such as, but not limited to, LAH and then removal of the benzyl group from the amine by procedures well familiar to those skilled in the art such as, but not limited to, hydrogenation. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R11 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R9 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
The 2,4-disubstituted pyrrolidines and 2,5-disubstituted piperidines of Formula VI and VIII may be synthesized as shown in Scheme 11. This procedure essentially follows the general protocols of Varea et. al., Tetrahedron Lett. 1995, 36, 1038 and references therein, with minor modification depending on A and B which should be readily recognized by one skilled in the art. For compounds of the general Formula VI, Intermediate 2 can be treated with a base such LDA, etc. and an alkylating agent Bxe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate R13, as defined in the scope. The cyano group of the intermediates can be removed with reagents such as, but not limited to, silver nitrite and sodium borohydride and the intermediates can then be oxidized with reagents such as, but not limited to, bromine. The intermediate can be treated with a base such as s-BuLi, etc. and an alkylating agent Axe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate R5, as defined in the scope. The synthesis is finished by the reduction of the lactam to the amine with a reagent such as, but not limited to, LAH and then removal of the benzyl group from the amine by procedures well familiar to those skilled in the art such as, but not limited to, hydrogenation. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R11 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R9 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
The 2,4-disubstituted piperidines of Formula VI and VIII may be synthesized as shown in Scheme 12. This procedure essentially follows the general protocols of Beak and Lee, J. Org. Chem. 1990, 55, 2578 and references therein, with minor modification depending on A and B which should be readily recognized by one skilled in the art. For compounds of the general Formula VI, 4-monosubstituted piperidines, synthesized as described above in Scheme 6 with A, which is R5 as defined in the scope, can be treated with a base such as s-BuLi, etc. and an alkylating agent Bxe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate R13, as defined in the scope. The BOC group was removed with reagents such as, but not limited to, TFA. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R11 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R9 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
The 3,4-disubstituted piperidines of Formula VI and VII may be synthesized as shown in Scheme 8. For compounds of the general Formula VI, Intermediate 3 can be treated with a base such LDA, etc. and an alkylating agent Bxe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate R6, as defined in the scope. The ketone may be modified to incorporate A, which is R5 as defined in the scope, by standard chemistry as described above in Scheme 6. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R9 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R9 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
The 2-monosubstituted piperazines, wherein B is H, and 2,5-disubstituted piperazines of Formula VIII may be synthesized as shown in Scheme 14. This procedure essentially follows the general protocols of Yonezawa et. al., Heterocycles 1997, 45, 1151 and references therein, with minor modification depending on A and B which should be readily recognized by one skilled in the art. Two amino acid derivatives are coupled by standard peptide coupling chemistry, well familiar to those skilled in the art and typical examples may be found in Richard C. Larock, Comprehensive Organic Transformations. The intermediate is reduced with reducing agents such as, but not limited to, LAH. The intermediate can be treated to amine modification conditions, as described previously in Schemes 2 and 3, to incorporate R14. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R11 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R11 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
The 2,6-disubstituted piperazines of Formula VIII may be synthesized as shown in Scheme 15. This procedure essentially follows the general protocols of Schanen et. al., Synthesis 1996, 833 and references therein, with minor modification depending on A and B which should be readily recognized by one skilled in the art. Intermediate 4 can be treated with a base such as t-BuLi, etc. and an alkylating agent Axe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate A. The amide is reduced with reagents such as, but not limited to, borane. The alcohol is alkylated with reagents such as, but not limited to, sodium hydride and methyl iodine. The intermediate can be treated with a base such as s-BuLi, etc. and an alkylating agent Bxe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate B. The benzyl group can be removed from the amine by procedures well familiar to those skilled in the art such as, but not limited to, hydrogenation. The unprotected amine can be treated to amine modification conditions, as described previously in Schemes 2 and 3, to incorporate R14. Alternatively, The unprotected amine can be treated with CBZ-Cl and then the BOC group can be removed and the other amine can be treated to amine modification conditions, as described previously in Schemes 2 and 3, to incorporate R14. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R11 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R11 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
The 2,3-disubstituted piperazines of Formula VIII may be synthesized as shown in Scheme 5. This procedure essentially follows the general protocols of Micouin et. al., Tetrahedron Lett. 1996, 37, 849 and references therein, with minor modification depending on A and B which should be readily recognized by one skilled in the art. Intermediate 4 can be treated with a base such as s-BuLi, etc. and an alkylating agent Axe2x80x94X where X is a halide (halide=Cl, Br, I), mesylate, tosylate, triflate, etc. to incorporate A. The compound can be treated with sodium hydride followed by B-metal which can a grinard reagent to incorporate the B group. The lactam can be reduced to the amine with a reagent such as, but not limited to, LAH and then removal of the benzyl group from the amine by procedures well familiar to those skilled in the art such as, but not limited to, hydrogenation. The unprotected amine can be treated to amine modification conditions, as described previously in Schemes 2 and 3, to incorporate R14. Alternatively, The unprotected amine can be treated with CBZxe2x80x94Cl and then the BOC group can be removed and the other amine can be treated to amine modification conditions, as described previously in Schemes 2 and 3, to incorporate R14. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R11 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R11 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
The 2-monosubstituted morpholines, wherein B is H, 3-monosubstituted morpholines, wherein A is H, and 2,5-disubstituted morpholines of Formula VIII may be synthesized as shown in Scheme 17. This procedure essentially follows the general protocols of Brown et. al., J. Pharm Pharmacol 1990, 42, 797 and references therein, with minor modification depending on A and B which should be readily recognized by one skilled in the art. Compounds of general Formula VIII are synthesized by treating epoxides with sulfated amino alcohols under basic conditions such as, but not limited to, sodium hydroxide in methanol. Compounds of Formula VIII in which A is hydroxyethyl or hydroxymethyl and B is R11 as defined in the scope or in which B is hydroxyethyl or hydroxymethyl and A is R11 as defined in the scope are produced with the same protocol with minor modification which should be readily recognized by one skilled in the art. 
2,6-disubstituted morpholines of Formula VIII may be synthesized as shown in Scheme 18. This procedure essentially follows the general protocols of Colucci et. al., J. Am. Chem. Soc. 1987, 109, 7915 and references therein, with minor modification depending on R11 which should be readily recognized by one skilled in the art. Compounds of general Formula VIII are synthesized by treating intermediate 6 with amino alcohols, with R11 as defined in the scope. The amino group is protected with an appropriate protecting group well familiar to those skilled in the art, and typical examples may be found in Greene, T and Wuts, P. G. M., Protecting Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991 and references therein. The ester functionality is reduced to the alcohol functionality by methods well familiar to those skilled in the art, and typical examples may be found in Richard C. Larock, Comprehensive Organic Transformations.
The compounds of this invention and their preparation can be understood further by the following working examples, which do not constitute a limitation of the invention.